Integrins are a functionally and structurally related group of receptors that interact with a wide variety of ligands including extracellular matrix glycoproteins, complement and other cells. Integrins participate in cell-matrix and cell-cell adhesion in many physiologically important processes including embryological development, hemostasis, thrombosis, wound healing immune and nonimmune defense mechanisms and oncogenic transformation. See Hynes, Cell, 48:549-554 (1987). The majority of integrins participating in dynamic cell adhesion, bind a tripeptide, arginine-glycine-aspartic acid (RGD), present in their ligand, causing cell adhesion. See Ruoslahti et al., Science, 238:491-497 (1987).
Mac-1 (CD11b/CD18) is an integrin receptor found predominantly on macrophages and granulocytes. Like all integrin receptors, Mac-1 is a heterodimeric, transmembrane glycoprotein composed of non-covalently associated alpha and beta subunits.
The alpha (.alpha.) and beta (.beta.) chains of Mac-1 have molecular weight of 170,000 and 95,000 daltons, respectively, and the Mac-1 .alpha. chain has been completely sequenced. See Corbi et al., J. Biol. Chem., 263:12403-12411 (1988). For a review of the integrin receptors, see Hynes, Cell, 48:549-554 (1987) .
Mac-1 mediates neutrophil/monocyte adhesion to vascular endothelium and phagocytosis of complement-opsonized particles. Antibodies to the Mac-1 receptor alter neutrophil function in vivo including inhibiting neutrophil migration into inflammatory sites. See Price et al., J. Immunol., 139:4174-4177 (1987). Mac1 also functions as a receptor for fibrinogen in a reaction linked to fibrin deposition on the monocyte surface. See Altieri et al., J. Cell Biol., 107:1893-1900 (1988); Wright et al., Proc. Natl. Acad. Sci. USA, 85:7734-7738 (1988); Trezzini et al., Biochem. Biophys. Res. Commun., 156:477-484 (1988) and Gustafson et al., J. Cell Biol., 109:377-387 (1989).
Fibrinogen is a complex molecule of approximately 340,000 daltons and consists of three pairs of subunit polypeptides, called the .alpha., .beta. and gamma chains. These individual chains are held together by several disulfide bonds. The proteolytic digestion of fibrinogen by plasmin produces fragments A, B, C, D and E, all having a molecular weight of less the 85,000 daltons. See Pizzo et al., J. Biol. Chem., 247:636-645 (1972).
Further proteolytic digestion of fibrinogen by plasmin produces a D.sub.30 fragment with a molecular weight of about 30,000 daltons containing portions of the .alpha., .beta. and gamma chains of fibrinogen. See Furlan et al., Biochim. Biophys. Acta., 400:95-111 (1975).
The deposition of fibrinogen on the leukocyte surface occurs in a variety of inflammatory responses such as delayed type hypersensitivity, incompatible transplant rejection and the physiopathology of vascular obstruction and atherogenesis. See Geczy et al., J. Immunol., 130:2743-2749 (1983); Hooper et al., J. Immunol., 126:1052-1058 (1981); Colvin et al., J. Immunol., 114:377-387 (1975); Hattler et al., Cell Immunology, 9:289-295 (1973); Gerrity, R. G., Am. J. Pathol., 103:181-190 (1981) and Am. J. Pathol., 103:191-200 (1981); and Shelley et al., Nature, 270:343-344 (1977).
Recently, the interaction of fibrinogen with the Mac-1 receptor of leukocytes has been postulated to be a dynamic cell adhesion reaction involving the recognition of the tripeptide RGD within fibrinogen by the Mac-1 receptor similar to the interaction of fibrinogen with the integrin receptors on platelets and endothelial cells. See Altieri et al., J. Clinic Invest., 78:968-976 (1986); Pytela et al., Science, 231:1559-1562 (1986) and Ruoslahti et al., Science, 238:491-497 (1987) and Cell, 44:517-518 (1986).